Med Oncol (2014) 31:861 DOI 10.1007/s12032-014-0861-3
ORIGINAL PAPER
Low serum levels of vitamin D in metastatic cancer patients: a case–control study Ahmet Taner Su¨mbu¨l • Ahmet Sezer • Gamze Kavvasog˘lu • Celal Yu¨cel Batmacı • Erhan Yengil • Abdullah Erman Yag˘ız • ¨ stu¨n • Cumali Go¨kc¸e I˙lhami Gu¨ltepe • Hu¨seyin Abalı • I˙hsan U
Received: 3 December 2013 / Accepted: 22 January 2014 / Published online: 4 February 2014 Ó Springer Science+Business Media New York 2014
Abstract Accompanying comorbidities observed during the cancer treatment usually affect the course and outcome of the therapy. Hypovitaminosis D, which is one of these conditions, is a resolvable problem, if recognized. In this study, we investigated whether the serum 25(OH)D levels of the patients who were presented to our outpatient clinic were different from the serum levels of the healthy population living in the same area. Our study included 90 patients who were presented to the Medical Oncology outpatient clinic and 90 age, gender, body mass index and ethnic origin matched controls without a known disease, who were presented to the outpatient clinics of the Departments of Internal Diseases and Family Medicine for routine controls. Blood count tests, detailed biochemistry A. T. Su¨mbu¨l (&) G. Kavvasog˘lu C. Y. Batmacı Division of Medical Oncology, Faculty of Medicine, Mustafa Kemal University, 31000 Antakya, Hatay, Turkey e-mail:
[email protected] A. Sezer H. Abalı Division of Medical Oncology, Faculty of Medicine, Bas¸ kent University, Ankara, Turkey E. Yengil Division of Family Medicine, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey A. E. Yag˘ız Department of Physical Therapy and Rehabilitation, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey I˙. Gu¨ltepe Division of Internal Diseases, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey ¨ stu¨n C. Go¨kc¸e I˙. U Division of Endocrine and Metabolic Diseases, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
tests (including serum levels of Cr, Ca and P), measurement of serum 25(OH)D levels and C-reactive protein were performed in serum samples of all of the patients and controls. Mean serum levels of 25(OH)D were 13.5 ng/ml (SD 5.1) in all cancer patients, 13.1 ng/ml (SD 4.2) in the patients who were presented for adjuvant therapy, 13.8 ng/ ml (SD 5.5) in the patients who were presented at metastatic stage and 18.4 ng/ml (SD 12.5) in the controls. Mean serum CRP levels were 5.4 mg/dl (SD 1.2) in the control group, 8.4 mg/dl (SD 4.3) in the adjuvant therapy group and 20.3 (SD 16.8) in the patients with metastatic disease. Generally, all cancer patients (p 0.003) and the patients with metastatic cancer (p 0.004) had lower serum 25(OH)D levels compared to controls, and there was an inverse correlation between serum 25(OH)D and CRP levels in patients with metastatic cancer (p 0.036). In metastatic cancer patients, hypovitaminosis D may be a comorbidity and it is recommended to consider during initial evaluation and follow-up. Because it might improve these patients quality of life and chemotherapy adherence. Keywords Metastatic cancer Serum 25(OH)D levels Comorbid conditions Inflammation
Introduction Cancer is a public health problem with incremental increase in incidence, and World Health Organization predicts that it will be the disease that leads to most of the deaths starting from 2020 [1]. The importance of the problem increased the interest toward this disease, and the advances in the cancer therapy achieved during the last 10 years prolonged the survival of these patients and led many of them to become chronic patients. Therefore, in the
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management of these patients, comorbid conditions have gained more importance as they affect both the quality of life and therapeutical compliance. Hypovitaminosis D is a common comorbid condition both in the general population and in cancer patients [2]. Vitamin D [25(OH)D] is a steroid hormone, which is mainly associated with calcium and phosphate metabolism and, thereby, with the functions and the structure of the musculoskeletal system. To date, many clinical and epidemiological studies showed a correlation between the low serum levels of 25(OH)D and the risk of cancer development, and furthermore, some other reports revealed an inverse correlation between serum levels of 25(OH)D and cancer prognosis [3–8]. Additionally, several studies demonstrated a correlation between serum levels of 25(OH)D and muscular pain and weakness, cognitive changes and increased incidence of depression in both the general population and cancer patients [9–11]. Although the studies performed to date did not clearly report an optimal threshold for low serum levels of 25(OH)D, normal levels are considered as 35–55 ng/ml, the levels below 30 ng/ml are considered as insufficiency, the levels below 20 ng/ml are considered as deficiency and the levels below 10 ng/ml are considered as severe deficiency [12–14]. However, serum levels of 25(OH)D may vary by the factors such as ethnicity, seasonality, geographical factors, age, gender, nutritional habits and body mass index (BMI); especially when it is screened in the healthy population, some regions and races may have the values below the reference values and it is generally recommended to treat the serum levels of serum 25(OH)D below 20 ng/ml, even if the patient is asymptomatic. There is not a specific recommendation for routine measurement of the 25(OH)D serum levels in cancer patients. Considering all these issues, in this study, we investigated whether the serum levels of 25(OH)D in the newly diagnosed cancer patients who were presented to our clinic were different from age-, gender- and BMI-matched healthy people residing in the same area and tried to find out the incidence of hypovitaminosis D in cancer patients.
Patients and methods We enrolled 90 patients older than 18 years who were presented to the Medical Oncology Outpatient Clinic of our hospital with newly diagnosed cancer between June and July 2013 and age, gender, BMI and ethnic origin matched 90 controls without a known disease, who were presented to the Internal Diseases and Family Health Outpatient Clinics for routine control visits. In both patient and control groups, the patients with nutritional problems, gastrointestinal complaints, acute or chronic renal failure, the history of drug use that might affect serum 25(OH)D, calcium
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and phosphorus levels or who had active infection were excluded. After registering their demographic features, blood counts, detailed biochemistry tests (including measurement of serum levels of Cr, Ca and P), serum 25(OH)D and C-reactive protein level measurements are performed in all patients and controls. Serum 25(OH)D levels were measured by chemiluminescent immunoassay (ADVIA Centaur and ADVIA Centaur XP systems). Consistent with the previous studies, serum levels of 25(OH)D equal to 20–30 ng/ml were considered as insufficiency, those equal to 10–20 ng/ml as deficiency and those \10 ng/ml as severe deficiency.
Statistical methods Statistical analyses were done using SPSS for Windows 15.0 (Statistical Package for Social Sciences) software package. Both descriptive and analytical statistics were used. Normal distribution of continuous variables was tested with Kolmogorov–Smirnov test. Intergroup comparisons were performed using Student’s t test and Mann– Whitney U test. The correlations between continuous variables were examined using Pearson’s coefficient of correlation. For all statistical data, p \ 0.05 was considered as significant.
Results The study included 90 patients and 90 age-, gender- and BMI-matched controls. Patient group included 44 (48.9 %) women and 46 (51.1 %) men. Median age was 57 years (min–max 32–86). Of the patients, 36 (40 %) were presented for adjuvant therapy and 54 (60 %) for palliative chemotherapy in the presence of metastatic disease. First, three leading causes of admittance are breast cancer in 21 patients (23.3 %), lung cancer in 15 patients (16.7 %) and colorectal cancer in 13 patients (14.5 %). Demographics and clinical findings of the patients are summarized in Table 1. Overall, in all cancer patients, mean serum levels of 25(OH)D were found to be 13.5 ng/ml (SD 5.1). When the patients were divided into groups by serum levels of 25(OH)D, 22 patients (24.4 %) had serum levels between 0 and 10 ng/ml, 54 (60 %) had between 10 and 20 ng/ml and 14 (15.6 %) had between 20 and 30 ng/ml. In the patients who were admitted for adjuvant therapy, mean serum levels of 25(OH)D were 13.1 ng/ml (SD 4.2) and 6 patients (16.7 %) had levels between 0 and 10 ng/ml, 27 (75 %) between 10 and 20 ng/ml and 3 (8.3 %) between 20 and 30 ng/ml. In the patients who were presented at metastatic stage, mean serum levels of 25(OH)D were found to be 13.8 ng/ml
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Table 1 Patient characteristics and demographic features Value
Median age (range)
57 (31–86)
Gender (%) Female
44 (48.9 %)
Male
46 (51.1 %)
The most common three diagnosis Breast cancer
21 (23.3 %)
Lung cancer
15 (16.7 %)
Colorectal cancer
13 (14.5 %)
Initial stage at diagnosis Localized disease
36 (40 %)
Metastatic disease
54 (60 %)
100,00
80,00
Serum 25(OH)D Levels
Parameter
60,00
40,00
20,00
0,00 Patient Group
(SD 5.5). Accordingly, serum levels of 25(OH)D were between 0 and 10 ng/ml in 16 (29.6 %) patients, between 10 and 20 ng/ml in 27 (50 %) patients and between 20 and 30 ng/ml in 11 (20.4 %) patients. When the control group was examined, mean value for serum levels of 25(OH)D was 18.4 ng/ml (SD 12.5) and serum levels of 25(OH)D were between 0 and 10 ng/ml in 18 (10 %) patients, between 10 and 20 ng/ml in 46 (25.6 %) patients, between 20 and 30 ng/ml in 16 (8.9 %) patients and above 30 ng/ml in 10 (5.6 %) patients. Mean serum CRP levels were 5.4 mg/dl (SD 1.2) in the control group, 8.4 mg/dl (SD 4.3) in the patients who were presented for adjuvant therapy and 20.3 (SD 16.8) in the patients who were presented with metastatic disease. The findings are summarized in Table 1. When we evaluated whether there is a difference between the patients with cancer and control group in terms of serum levels of 25(OH)D, we found that serum levels of 25(OH)D were statistically significantly lower in cancer patients compared to controls (p 0.003). This difference was shown in Fig. 1. Subsequently, the difference between the cancer patients who were presented for adjuvant therapy and control group was evaluated, and no statistically significant difference was found (p 0.237). When the cancer patients with metastasis and their control group were compared, we saw that serum levels of 25(OH)D were statistically significantly lower in the patients with metastatic cancer compared to controls (p 0.004). While there was no difference of serum Ca and P levels between the patients who were presented for adjuvant therapy and those who were presented at metastatic stage, serum CRP levels were statistically significantly higher in the patients who were presented with metastatic cancer compared to those who were presented for adjuvant therapy (p 0.028). We also checked the existence of correlation between serum 25(OH)VitD levels and CRP levels in patients with metastatic cancer, and we
Control Group
Fig. 1 Serum 25(OH)D difference between patient and control group
Fig. 2 Correlation between serum 25(OH)D and CRP levels in patients with metastatic cancer
find statistically significant inverse correlation (p 0.036). This inverse correlation is shown in Fig. 2.
Discussion The patients with cancer, which is becoming a chronical disease gradually, require multifaceted evaluation, and many medical oncologists may overlook or ignore additional medical problems other than cancer, commonly leading to impaired quality of life and decreased chemotherapy compliance among the patients. Hypovitaminosis D, which is one of these accompanying comorbidities, is a
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common problem worldwide and is a condition that affects human health and quality of life with a broad range of outcomes, ranging from impaired musculoskeletal functions to cognitive and psychiatric disorders [15–17]. The current literature contains mostly retrospective studies about hypovitaminosis D in various types of cancer, and there is still a lack of recommendation for routine measurement of serum 25(OH)D levels in the patients with cancer. While some of these studies investigated its correlation with cancer development, others examined its correlation with the prognosis [18–22]. However, as far as we know, its incidence among the patients with early stage and advanced stage cancer and the difference between the incidence observed in the healthy population and in cancer patients have not been investigated in any prior study by comparing with the serum levels obtained in the healthy population living in the same area (25–27). In our study, cancer patients and metastatic cancer patients who were living in the same area during the same seasonal period showed statistically significant lower serum levels of 25(OH)D compared to age-, gender- and BMI-matched controls, but this difference was not statistically significant in the patients who were presented for adjuvant therapy. In the studies performed on the patients with metastatic cancer, the incidence of vitamin D deficiency was generally about 60 %, but the incidence of vitamin D insufficiency was reported to be about 80 % (7.27). In our study, these rates were found to be 79.6 and 100 %, respectively, among the patients with metastatic cancer. In our opinion, although we have enrolled the patients who are not likely to be exposed to factors that may affect the serum levels of 25(OH)D in our study, this result that we obtained renders this study more valuable. In the patients with metastatic cancer, low serum levels of 25(OH)D may result from many factors, ranging from the changes in nutritional habits and amount of sun exposure, which begun before the diagnosis, to chronic inflammation (2,28,29). In our patients, C-reactive protein, which is an inflammatory marker, levels were near normal in all controls, whereas they were statistically significantly higher in the patients with metastatic cancer compared to controls, and there was an inverse correlation between serum 25(OH)D and CRP levels. Increased inflammation should be one of the causes of lower serum 25(OH)D levels in these patients and maybe during follow-up resolving of inflammation can be associated with increasing of serum 25(OH)D levels without any therapy? Prospective studies with larger populations can be conducted to research this hypothesis. The gradual increase in the incidence of cancer within the last 10 years led to an incremental increase in the precautions taken against this problem and in the number of therapeutic modalities. The advances achieved in our fight against cancer during the last decade resulted in an
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increase in cure rates of various subtypes of cancer and to prolonged life expectancy in metastatic diseases. Being especially marked in metastatic diseases, this success results from more common use of conventional, new-generation, targeted and personalized chemotherapeutical agents. To achieve such a success, chemotherapy compliance of the patient and maintenance of the quality of life during the treatment are among the most important factors. From this point of view, in patients with metastatic disease, given the role of serum levels of 25(OH)D in the musculoskeletal functions, its effects on fatigue and cognitive functions, which commonly affect both quality of life and chemotherapy compliance, should absolutely be considered. Although it is a treatable condition, which is thought by many medical oncologists to be associated with underlying cancer or side effects of the drugs used, it may affect the patient and the disease management and may have adverse outcomes for both the patient and the physicians’ management. Main limitation of our study is the fact that it was conducted at a single center in a region. Similar future studies that will be conducted in multiple centers in different regions will allow to demonstrate more clearly whether routine measurement of serum 25(OH)D levels at the time of diagnosis is necessary and to understand the effects of the replacement therapies on the prognosis of the cancer patients. In summary, in metastatic cancer patients, hypovitaminosis D may be a comorbidity and it is recommended to consider during initial evaluation and follow-up. Because it might improve these patients quality of life and chemotherapy adherence. Conflict of interest The authors of this manuscript have no conflicts of interest to disclose. The authors have full control of all the primary data and agree to allow the journal to review the data if requested.
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